High efficacy of PD-1 inhibitor after initial failure of PD-L1 inhibitor in Relapsed/Refractory classical Hodgkin Lymphoma.

PURPOSE: We sought to understand the clinical course and molecular phenotype of patients who showed disease progression after programmed cell death ligand 1 (PD-L1) inhibitor treatment but subsequently responded to PD-1 inhibitor treatment. We also explored the response to PD-1-axis targeted therapy of classical Hodgkin lymphoma (cHL) according to genetically driven PD-L1 and programmed cell death ligand 2 (PD-L2) expression. METHODS: Five patients in a phase II clinical trial of CS1001 (PD-L1 inhibitor) for relapsed or refractory (R/R) cHL were retrospectively reviewed. Formalin-fixed, paraffin-embedded whole tissues from the five patients were evaluated for 9p24.1 genetic alterations based on FISH and the expression of PD-L1, PD-L2, PD-1, major histocompatibility complex (MHC) class I-II, and the tumor microenvironment factorsCD163 and FOXP3 in the microenvironmental niche, as revealed by multiplex immunofluorescence. RESULTS: All five patients showed primary refractory disease during first-line treatment. Four patients received PD-1 inhibitor after dropping out of the clinical trial, and all demonstrated at least a partial response. The progression-free survival ranged from 7 to 28 months (median = 18 months), and 9p24.1 amplification was observed in all five patients at the PD-L1/PD-L2 locus. PD-L1 and PD-L2 were colocalized on Hodgkin Reed-Sternberg (HRS) cells in four of the five (80%) patients. There was differential expression of PD-L1 and PD-L2 in cells in the tumor microenvironment in cHL, especially in HRS cells, background cells and tumor-associated macrophages. CONCLUSIONS: PD-L1 monotherapy may not be sufficient to block the PD-1 pathway; PD-L2 was expressed in HRS and background cells in cHL. The immunologic function of the PD-L2 pathway in anti-tumor activity may be underestimated in R/R cHL. Further study is needed to elucidate the anti-tumor mechanism of PD-1 inhibitor and PD-L1 inhibitor treatment.

Prophylactic antibiotic treatment with TMP-SMX decreased the incidence of interstitial pneumonia in patients with B-cell lymphoma on chemotherapy.

BACKGROUND: Several studies have reported the incidence of interstitial pneumonia (IP) among patients with non-Hodgkin lymphoma (NHL) that are undergoing combination chemotherapy plus rituximab; however, the effective prophylactic treatment for IP remains unclear. This study aims to explore the prophylactic effect of trimethoprim-sulfamethoxazole (TMP-SMX) on IP and identify IP-associated risk factors in NHL patients. METHODS: Between March 2013 and April 2018, 498 patients (264 males, 53%) with B-cell NHL undergoing first-line RCHOP-like chemotherapy treatment with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone were enrolled in this study. RESULTS: These patients had a median age of 56 years, and 311 of the 498 patients (62.4%) were administered once daily with the prophylactic treatment of TMP-SMX. IP occurred in 65 patients (13.1%), indicating a significant reduction in the IP incidence rate (21.4% vs. 8.0%; p < 0.001). Among patients treated with TMP-SMX, 2 (1.2%) exhibited rashes, 38 (12.2%) suffered from nausea and vomiting, 52 (16.7%) showed signs of neutropenia, and 18 (5.8%) suffered from kidney dysfunction. Both univariate and multivariate analysis showed that gender (male), history of diabetes, and absence of prophylactic TMP-SMX treatment were significant risk factors associated with IP. Disease progression was observed in 55/311 (17.7%) patients that underwent prophylactic TMP-SMX treatment and in 63/187 (33.7%) patients that did not (p < 0.001). CONCLUSIONS: This study revealed that the occurrence of IP was common in B-cell NHL patients undergoing combined chemotherapy plus rituximab treatment. IP could be reduced with prophylactic treatment of once-daily oral TMP-SMX.

Long non-coding RNA NEAT1 serves as a novel biomarker for treatment response and survival profiles via microRNA-125a in multiple myeloma.

BACKGROUND: The present study aimed to explore the association of long non-coding RNA nuclear paraspeckle assembly transcript 1 (lncRNA NEAT1) with multiple myeloma (MM) risk and further investigate its correlation with clinical features, treatment response, survival profiles, and its interaction with microRNA-125a (miR-125a) in MM patients. METHODS: Totally, 114 de novo symptomatic MM patients and 30 healthy donors (as controls) were recruited. Their bone marrow samples were collected before treatment (MM patients) and at enrollment (healthy donors), respectively. Subsequently, plasma cells were isolated from bone marrow for detection of lncRNA NEAT1 and miR-125a expression via reverse transcription quantitative polymerase chain reaction. RESULTS: lncRNA NEAT1 was upregulated in MM patients compared with healthy donors and presented with excellent value in distinguishing MM patients from healthy donors. In MM patients, lncRNA NEAT1 positively associated with International Staging System (ISS) stage, beta-2 microglobulin (ß2-MG), and lactate dehydrogenase (LDH), but not correlated with core cytogenetics and other clinical features. Furthermore, lncRNA NEAT1 negatively associated with complete remission (CR), overall remission rate (ORR), progression-free survival (PFS), and overall survival (OS). Moreover, lncRNA NEAT1 negatively associated with miR-125a in MM patients. MiR-125a was downregulated in MM patients compared with healthy donors, and it negatively associated with ISS stage, ß2-MG, and LDH, but positively correlated with CR, ORR, PFS, and OS in MM patients. CONCLUSION: lncRNA NEAT1 might interact with miR-125a, and serves as a novel biomarker for treatment response and survival profiles in MM, indicating its clinical value for MM management.

Clinical features and biological implications of different U2AF1 mutation types in myelodysplastic syndromes.

U2AF1 mutations (U2AF1MT) occur commonly in myelodysplastic syndromes (MDS) without ring sideroblasts. The aim of this study was to investigate the clinical and biological implications of different U2AF1 mutation types in MDS. We performed targeted gene sequencing in a cohort of 511 MDS patients. Eighty-six patients (17%) were found to have U2AF1MT, which occurred more common in younger patients (P = .001) and represented ancestral lesions in a substantial proportion (71%) of cases. ASXL1MT and isolated +8 were significantly enriched in U2AF1MT-positive cases, whereas TP53MT, SF3B1MT, and complex karyotypes were inversely associated with U2AF1MT. U2AFS34 subjects were enriched for isolated +8 and were inversely associated with complex karyotypes. U2AF1MT was significantly associated with anemia, thrombocytopenia, and poor survival in both lower-risk and higher-risk MDS. U2AF1S34 subjects had more frequently platelet levels of <50 × 109 /L (P = .043) and U2AF1Q157 /U2AF1R156 subjects had more frequently hemoglobin concentrations at <80 g/L (P = .008) and more often overt fibrosis (P = .049). In conclusion, our study indicates that U2AF1MT is one of the earliest genetic events in MDS patients and that different types of U2AF1MT have distinct clinical and biological characteristics.

Impact of positive CD4 cells on event-free survival in follicular lymphoma patients.

OBJECTIVE: Previous results about prognostic value of CD4+ T cells in follicular lymphoma (FL) remain controversial. METHODS: Immunohistochemistry was used to examine expression of positive CD4 cells in 103 patients with FL 1-3A. Early failure was described as failing to achieve event-free survival (EFS) at 12 or 24 months. RESULTS: There were 49 (47.6%) male and 54 (52.4%) females, with a median age of 54 years. Compared to patients with <20% of positive CD4 cells, patients with ≥20% of positive CD4 cells exhibited a significant lower risk of early failure (2-year EFS rate: 56.7% vs 73.5%, p = 0.047). When patients were stratified based on positive CD4 cell combined with FLIPI, the median EFS (p = 0.002) and median OS (p = 0.007) were significantly different. CONCLUSIONS: This study demonstrated that higher expression of positive CD4 cells predicts lower risk of early failure in follicular lymphoma, and combination analysis of CD4 and FLIPI could better predict disease relapse and survival outcome.

The Prognostic Utility of 18F-Fluorodeoxyglucose Positron Emission Tomography-Computed Tomography-Based Analyses of Metabolic Response Rates in Newly Diagnosed Diffuse Large B Cell Lymphoma Patients.

Background: Roughly one third of diffuse large B cell lymphoma (DLBCL) patients experience relapsed or refractory disease, and their prognosis is unsatisfactory. It is thus important to identify patients who respond poorly to first-line treatment. Some studies have evaluated the prognostic value of interim PET-CT (iPET-CT) or end-of-treatment PET-CT (ePET-CT) in lymphoma patients, but there have been few studies exploring the prognostic value of metabolic response rates in the evaluation of DLBCL patients. Methods: Consecutive newly diagnosed DLBCL patients were screened from March 2013 to June 2020. Patients received at least four cycles of chemotherapy, and underwent baseline, iPET-CT and ePET-CT scanning. Kaplan-Meier survival curves with log-rank tests were employed to assess survival outcomes including overall survival (OS) and progression-free survival (PFS). Independent predictors of survival were identified through univariable and multivariable Cox regression analyses. Results: 307 patients were evaluated. At the time of iPET-CT scanning, 250, 45, and 12 patients exhibited complete response (CR), partial response (PR), and stable disease (SD)/progressive disease (PD), respectively. The percentage of negative iPET-CT was 81.4% (250/307). Among 295 patients with ePET-CT, 262 (88.8%) achieved negativity and 33 (11.2%) exhibited positivity including 26 PR and 7 PD. The 2-year PFS and 2-year OS for patients with iPET-CT positivity were 50.7% and 76.5%, respectively, and were significantly shorter than those for patients with iPET-CT negativity (2-year PFS 82.7%, p<0.001; 2-year OS 94.2%, p<0.001). Patients with ePET-CT positivity had significant poorer 2-year PFS (48.1%) and 2-year OS (78.5%) compared with those ePET-CT negativity (2-year PFS 83.8%, p<0.001; 2-year OS 94.9%, p<0.001). The positivity rates on iPET-CT and ePET-CT evaluation were significantly higher in patients in the high/high-intermediate risk group compared with patients in the low/low-intermediate group. In a multivariable analysis, high/high-intermediate international prognostic index (IPI) and ePET-CT positivity were independently associated with poor PFS and OS. Conclusions: Our results suggest that the speed of metabolic response to treatment is of limited prognostic value in newly diagnosed DLBCL patients. Patients exhibiting PR at iPET-CT evaluation should carefully consider whether to change chemotherapy regimen.

Distinct Molecular Subtypes of Diffuse Large B Cell Lymphoma Patients Treated with Rituximab-CHOP Are Associated with Different Clinical Outcomes and Molecular Mechanisms.

OBJECTIVE: Our purpose was to characterize distinct molecular subtypes of diffuse large B cell lymphoma (DLBCL) patients treated with rituximab-CHOP (R-CHOP). METHODS: Two gene expression datasets of R-CHOP-treated DLBCL patients were downloaded from GSE10846 (n = 233, training set) and GSE31312 (n = 470, validation set) datasets. Cluster analysis was presented via the ConsensusClusterPlus package in R. Using the limma package, differential expression analysis was utilized to identify feature genes. Kaplan-Meier survival analysis was presented to compare the differences in the prognosis between distinct molecular subtypes. Correlation between molecular subtypes and clinical features was analyzed. Based on the sets of highly expressed genes, biological functions were explored by gene set enrichment analysis (GSEA). Several feature genes were validated in the molecular subtypes via qRT-PCR and western blot. RESULTS: DLBCL samples were clustered into two molecular subtypes. Samples in subtype I displayed poorer overall survival time in the training set (p < 0.0001). Consistently, patients in subtype I had shorter overall survival (p = 0.0041) and progression-free survival time (p < 0.0001) than those in subtype II. Older age, higher stage, and higher international prognostic index (IPI) were found in subtype I. In subtype I, T cell activation, lymphocyte activation, and immune response were distinctly enriched, while cell adhesion, migration, and motility were significantly enriched in subtype II. T cell exhaustion-related genes including TIM3 (p < 0.001), PD-L1 (p < 0.0001), LAG3 (p < 0.0001), CD160 (p < 0.001), and CD244 (p < 0.001) were significantly highly expressed in subtype I than subtype II. CONCLUSION: Two molecular subtypes were constructed in DLBCL, which were characterized by different clinical outcomes and molecular mechanisms. Our findings may offer a novel insight into risk stratification and prognosis prediction for DLBCL patients.